37 Novel Risk Loci Have Been Identified for Parkinson Disease
A total of 37 novel risk loci have been identified for Parkinson disease following an analysis of the largest aggregate of genome-wide association studies data.
This meta-analysis included 17 datasets from Parkinson disease genome-wide association studies available from European ancestry samples. All available data was used to estimate heritable risk and develop predictive models of heritability.
Included in the researchers’ analysis were 7.8 million single nucleotide polymorphisms in 37,688 patients with Parkinson disease, 18,618 individuals in the UK Biobank who did not have Parkinson disease but had a first-degree relative who did, and 1.4 million controls.
After analyzing the data, the researchers identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci.
“These 90 variants explained 16% to 36% of the heritable risk of Parkinson's disease depending on prevalence,” the researchers wrote.
The researchers also performed a Mendelian randomization to examine shared genetic risk between Parkinson disease and other phenotypes. Methylation and expression data were then input into the framework; this analysis found putatively associated genes at 70 risk signals underlying genome-wide association studies loci for follow-up functional studies.
The Mendelian randomization also found a robust association between cognitive performance and Parkinson disease (p = 8.00 × 10 −7).
The researchers then performed tissue-specific expression-enrichment analyses, which suggested that Parkinson-disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single-cell data.
In addition, the researchers found significant genetic correlations with brain volumes, smoking status, and educational attainment.
“These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified,” the researchers concluded. “These associations derived from European ancestry datasets will need to be followed-up with more diverse data.”
Nalls MA, Blauwedraat C, Vallerga CL, et al; 23andMe Research Team, System Genomics of Parkinson's Disease Consortium, and the International Parkinson's Disease Genomics Consortium. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 2019;18(12):1091-1102. https://doi.org/10.1016/S1474-4422(19)30320-5.